PROJECT SUMMARY ? PROJECT 1 Project 1 will focus on using ?omics derived datasets to elucidate genetic factors and transcripts to predict the pathways and networks underlying the etiology of Lewy body dementia (LBD). Aim 1 will build upon the investigators previous studies. Our work has shown that the established common genetic susceptibility variants do not drive either the ?-syn or A? pathologic burden or the degree of neuronal cell loss observed in Lewy body disorders. These data suggest that the genes and variants that drive disease progression and burden of pathology may be different from those variants that increase the risk of disease. To examine this hypothesis, we will analyze whole-genome sequence data for association with ?-syn or A? pathologic burden and neuronal cell loss in the nigra, and additional neuropathologic measures (as generated through the Pathology Core [Core B]) for over 500 cases of our Lewy Body disease series. To complement these studies Aim 2 will perform bulk RNA-Seq across all of the pathologic cases with varying levels of ?-syn or A? burden, in an unbiased approach, assess the levels of transcripts that are related to synuclein burden. In addition, a subset of cases will be analyzed using single-nucleus RNAseq to examine the relationship between transcript level and ?-syn or A? pathologic burden categorized into distinct groups by Core B PI Dr. Dickson. These Aims will help describe the genomic architecture driving LBD heterogeneity. The final Aim 3 will use these data to model networks due to different LBD pathologies and to predict disease drivers. Aim 3 will also incorporate ?omics data generated within Project 2. Functional characterization of candidate genes, transcript and pathways genes and the interaction with ?-syn or A? and cellular readouts (e.g. autophagy, lysosomal dysfunction) will be performed in collaboration with the PIs of Project 4.